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Rohit K Jain, William Paul Skelton IV, Jingsong Zhang Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USACorrespondence: Jingsong ZhangDepartment of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL 33612, USAEmail Jingsong.zhang@moffitt.orgAbstract: Enfortumab vedotin (EV) is an antibody–drug conjugate with humanized anti-Nectin-4 antibody linked with a microtubule-disrupting agent called monomethyl auristatin E. Nectin-4 is a cellular adhesion protein that is overexpressed in urothelial cancer. EV was approved in December 2019 for patients with locally advanced or metastatic urothelial cancer who previously received platinum-based chemotherapy and immune checkpoint inhibitors. Here, we reviewed the clinical efficacy and safety data that led to the accelerated approval of EV for treating patients with metastatic urothelial cancer. Emerging clinical data on EV-based combinational therapeutic trials for metastatic urothelial cancer were also reviewed.Keywords: enfortumab vedotin, urothelial cancer, antibody-drug conjugate

Rohit K Jain, Hongbin Chen Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA Abstract: In the last decade, there have been major therapeutic advances in the management of patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer. Crizotinib was the first approved ALK inhibitor with significant benefits over chemotherapy. However, patients inevitably develop disease progression especially in central nervous system and acquire resistance to crizotinib. Several next-generation ALK inhibitors have been developed to overcome these resistance mechanisms and have demonstrated clinical benefits in crizotinib-refractory non-small cell lung cancer including in central nervous system. Brigatinib is a second-generation ALK inhibitor with high level of activity against ALK and several other targets. It is active in vitro against many ALK kinase domain mutations including L1196M, E1210K, and G1202R which may mediate acquired resistance to other ALK inhibitors. In Phase I/II and ALTA clinical studies, brigatinib has demonstrated substantial and durable responses and intracranial responses after progression on crizotinib. It has acceptable safety profile, but early pulmonary toxicity has been observed prompting to pursue daily dosing of 180 mg (with lead-in). Overall, 180 mg (with lead-in) has showed consistently better efficacy than 90 mg. In this review, we will discuss in detail these two pivotal trials that led to the accelerated approval for brigatinib and its future directions. Keywords: non-small cell lung cancer, ALK rearrangement, crizotinib, ceritinib, alectinib, brigatinib

INTRODUCTION: The present study was performed to compare cemented total hip replacement (THR) with cemented bipolar prosthesis in the treatment of displaced fracture neck of femur in elderly patients. MATERIALS AND METHODS: This prospective study included 47 patients of greater than 60 years of age and having fracture of neck of femur, out of which 25 patients were managed by cemented bipolar prosthesis and remaining 22 were managed by cemented THR between June 2011 and June 2013. These patients were followed up post-operatively for two years, at 6, 12 and 24 months, for functional analysis using Modified Harris Hip Score. RESULTS: Modified Harris Hip Score was significantly higher in the THR group as compared to the bipolar prosthesis group at 6, 12 and 24 months post-operatively. Pain was almost similar in both the groups at all follow-up periods. Gait and range of motion was significantly higher in THR group as compared to bipolar prosthesis group at all-time point intervals. CONCLUSION: Cemented THR is a better option as compared to cemented bipolar prosthesis based on our short term functional outcome for the management of fracture of neck of femur in elderly patients.

Background: Occurrence of concurrent traumatic brain injury and aortic injury is rare and potentially fatal trauma pattern. The incidence of traumatic brain injury associated with aortic injury is likely to be underestimated because many patients with this pathology die prior to hospital admission or imaging study. Even after diagnosis, there are difficulties in managing such a patient as different approaches are required to treat each of them. Case report: A 68-year-old man with head injury and blunt chest injury was operated. He had right frontotemporal subarachnoid haemorrhage with fracture of left temporal bone with hemopneumothorax and multiple rib fractures on the left side of the chest. Patient was evaluated with plain CT scan and CT angiogram of brain. Contrast enhanced CT scan of chest revealed rupture of the arch of aorta. Head injury was managed conservatively and emergency aortic stent grafting was done. Discussion and conclusion: Aortic injury may be missed, so the emergency physician should have high index of suspicion while dealing with polytrauma patient instead of just focussing on head injury. Head injury and aortic injury occurring together need different treatment methods which can have conflict. (A) In aortic injury, maintaining a lower systolic blood pressure is essential to prevent further haemorrhage. On the contrary blood pressure should be maintained at normal level for adequate cerebral perfusion in head injury. (B) Sedation required for aortic injury can interfere with the clinical assessment of a patient with traumatic brain injury. (C) Anticoagulants used in the treatment of aortic injury are usually contraindicated in head injury. The treatment needs a team approach by neurosurgeon, endovascular cardiologist, cardiac surgeon, emergency physician, and critical care intensivist etc., to manage patients of traumatic brain injury with aortic injury.

Occupants are active participants in their built environment, affecting its performance while simultaneously being affected by its design and indoor environmental conditions. With recent advances in computer modeling, simulation tools, and analysis techniques, topics such as human-building interactions and occupant behavior have gained significant interest in the literature given their premise of improving building design processes and operating strategies. In practice, the focus of occupant-centric literature has been mostly geared towards the latter (i.e., operation), leaving the implications on building design practices underexplored. This paper fills the gap by providing a critical review of existing studies applying computer-based modeling and simulation to guide occupant-centric building design. The reviewed papers are organized along four main themes, namely occupant-centric: (i) metrics of building performance, (ii) modeling and simulation approaches, (iii) design methods and applications, and (iv) supporting practices and mechanisms. Important barriers are identified for a more effective application of occupant-centric building design practices, including the limited consideration of metrics beyond energy efficiency (e.g., occupant well-being and space planning), the limited implementation and validation of the proposed methods, and the lack of integration of occupant behavior modeling in existing building performance simulation tools. Future research directions are discussed, covering large-scale international data collection efforts to move from generic assumptions about occupant behavior to specific/localized knowledge, improved metrics of measuring building performance, and improved industry practices, such as building codes, to promote an occupant-in-the-loop approach to the building design process.

Background Objectives: Co-infection of dengue virus and acute hepatitis A virus in paediatric population is a major health concern in endemic countries. This cross sectional retrospective study was conducted to evaluate the prevalence of hepatitis A virus among the clinically dengue suspected paediatric cases presented at our tertiary care centre during the two-year period (2022-2023)., Methods: A total of 747 dengue suspected paediatric clinical specimens were included in this study. Serological diagnosis of DENV and HAV was done using Dengue IgM capture ELISA kit and anti-HAV IgM ELISA kits., Results: Out of the 747 dengue suspected paediatric patients, 245 (32.8%) were seropositive for either DENV, HAV, or both viruses and among these 135 (18.07%) were positive for DENV, 110 (14.72%) were positive for HAV, 22 (2.94%) were co-infected with both DENV and HAV. Further, among DENV seronegative cases, 88 (11.78%) clinical samples were found to be HAV positive. Among all the age groups, the highest prevalence of DENV and HAV was observed in 6-10 yrs. The monsoon season observed the highest number of seropositive cases compared to winter season and summer seasons. Fever was found to be most prevalent clinical symptom followed by nausea/vomiting and stomach discomfort., Interpretation Conclusion: This study underlines the significance of differential diagnosis for the detection of concurrently transmitted viral diseases during the common seasons in the endemic areas. Diagnostic challenges like misdiagnosis events can be solved by advising differential diagnosis especially in paediatric cases., (Copyright © 2025 Journal of Vector Borne Diseases.)

There is a critical unmet need for safe and efficacious neoadjuvant treatment for cisplatin-ineligible patients with muscle-invasive bladder cancer. Here we launched a phase 1b study using the combination of intravesical cretostimogene grenadenorepvec (oncolytic serotype 5 adenovirus encoding granulocyte-macrophage colony-stimulating factor) with systemic nivolumab in cisplatin-ineligible patients with cT2-4aN0-1M0 muscle-invasive bladder cancer. The primary objective was to measure safety, and the secondary objective was to assess the anti-tumor efficacy as measured by pathologic complete response along with 1-year recurrence-free survival. No dose-limiting toxicity was encountered in 21 patients enrolled and treated. Combination treatment achieved a pathologic complete response rate of 42.1% and a 1-year recurrence-free survival rate of 70.4%. Pathologic response was associated with baseline free E2F activity and tumor mutational burden but not PD-L1 status. Although T cell infiltration was broadly induced after intravesical oncolytic immunotherapy, the formation, enlargement and maturation of tertiary lymphoid structures was specifically associated with complete response, supporting the importance of coordinated humoral and cellular immune responses. Together, these results highlight the potential of this combination regimen to enhance therapeutic efficacy in cisplatin-ineligible patients with muscle-invasive bladder cancer, warranting additional study as a neoadjuvant therapeutic option. ClinicalTrials.gov identifier: NCT04610671 ., Competing Interests: Competing interests: R.L. reports research support from Predicine, Veracyte, CG Oncology, Valar Labs, Merck and Janssen; clinical trial protocol committee participation with CG Oncology, Merck and Janssen; and is scientific advisor/consultant for Bristol Myers Quibb, Merck, Fergene, Arquer Diagnostics, Urogen Pharma, Lucence, CG Oncology, Janssen, Thericon, Iconovir, ImmunityBio and Pfizer. W.J.S. reports consultant work for Pacific Edge and Urogen Pharma. P.E.S. reports being the Vice Chair of the NCCN guidelines committee for bladder and penile cancer. J.Z. reports consultant work for Sanofi, AstraZeneca, Dendreon, Seagen, Bayer and Pfizer. G.D.G. reports consultant work for MyCareGorithm and stock options in Lantheus. J.M.B. reports consultant work for CG Oncology and Kalivir Immunotherapeutics and being a shareholder of CG Oncology and Kalivir Immunotherapeutics. C.P.N.D. reports consultant work for AstraZeneca and CG Oncology and intellectual property ownership related to the use of genetic alterations as a predictive biomarker for response to nadofaragene firadenovec. R.K.J. reports consultant work for AVEO, Bristol Myers Squibb, Sanofi, EMD Serono, Gilead Sciences, IDEOlogy Pfizer and Seattle Genetics/Astellas; speaker’s bureau for Gilead Sciences, Seagen and Seattle Genetics/Astellas; research funding from Bristol Myers Squibb, Gilead Sciences and the National Cancer Institute; and honoraria from FLASCO, Curio Science, DAVA Oncology, NCCN/Pfizer and OncLive/MJH Life Sciences. J.J.M. reports membership on the CG Oncology Board of Directors; being the Associate Center Director at Moffitt Cancer Center; ownership interest in Aleta Biotherapeutics, CG Oncology, Turnstone Biologics, Ankyra Therapeutics and AffyImmune Therapeutics; and consultant work for ONCoPEP, CG Oncology, Turnstone Biologics, Vault Pharma, Ankyra Therapeutics, AffyImmune Therapeutics, UbiVac, Vycellix and Aleta Biotherapeutics. J.R.C.-G. reports consultant work for Anixa Biosciences and Alloy Therapeutics; stock options in Compass Therapeutics, Anixa Biosciences and Alloy Therapeutics; patent licensed by Anixa Biosciences; intellectual property filed with Compass Therapeutics; and being the co-founder of Cellepus Therapeutics, a CAR T cell company. The other authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

To have the desired therapeutic effect, nanomedicines and macromolecular medications must move from the site of injection to the site of action, without having adverse effects. Transvascular transport is a critical step of this navigation, as exemplified by the Enhanced Permeability and Retention (EPR) effect in solid tumors, not found in normal organs. Numerous studies have concluded that passive, diffusion- and convection-based transport predominates over active, cellular mechanisms in this effect. However, recent work using a new approach reevaluated this principle by comparing tumors with or without fixation and concluded the opposite. Here, we address the controversy generated by this new approach by reporting evidence from experimental investigations and computer simulations that separate the contributions of active and passive transport. Our findings indicate that tissue fixation reduces passive transport as well as active transport, indicating the need for new methods to distinguish the relative contributions of passive and active transport.

Atomistic simulations of peptoids have the capability to predict structure-property relationships, depending on the accuracy of the associated force field. This work presents an addendum to the CGenFF-NTOID peptoid force field for aliphatic side chains. We develop parameters for two aliphatic side chains, R N 1-tertiary butylethyl glycine ( r1tbe ) and S N 1-tertiary butylethyl glycine ( s1tbe ). Enhanced sampled (well-tempered metadynamics) atomistic simulations are performed using CGenFF-NTOID to determine the monomer structural preferences for these side chains. The free energy minima attained through these simulations are compared with structural observations obtained from experiments. We also compare the structural preferences of aliphatic s1tbe and aromatic S N 1-naphthylethyl glycine ( s1ne ). This is done through parallel bias metadynamics on monomers and pentamers of s1tbe and s1ne . The structural observations through simulations are also compared with available experimental metrics of the dihedral angles and pitch. The pentamer minima structures are also compared with ab initio optimized structures, which show excellent agreement. This comparison illustrates alternatives to aromatic side chains that can be used to stabilize peptoid secondary structures. The developed parameters help to increase the diversity of peptoid side chains available for materials discovery through computational studies.

Background: Ovarian cancer (OvCa) is the most lethal of the gynecologic malignancies. Immune checkpoint inhibitors, which have revolutionized the treatment of multiple malignancies, have had limited efficacy in OvCa patients. This lack of effectiveness is partly due to the abnormal ovarian tumor microenvironment (TME), displaying a desmoplastic, highly fibrotic extracellular matrix. High extracellular matrix deposition leads to a buildup of compressive forces that cause tumor blood vessel collapse, reduced vessel perfusion, poor delivery of drugs, and compromised trafficking of cytotoxic T-cells to these tumors., Methods: Using two syngeneic OvCa models, we tested the effect of losartan, a widely prescribed anti-hypertensive drug, on reprogramming the TME and chemosensitizing the cancer cells., Results: Losartan treatment (i) reprograms the TME leading to increased vascular perfusion, and thus enhances drug delivery and immune effector cell intratumoral infiltration and function; and (ii) rewires the OvCa cells by suppressing the IGF-1 signaling, resulting in enhanced chemosensitivity. As a result of the combined tumor and stromal effects, losartan treatment enhances the efficacy of chemo-immunotherapy in OvCa models., Conclusion: The safety and low cost ( < $1-2/day) of losartan warrant rapid translation of our findings to patients with OvCa., Competing Interests: Competing interests R.K.J. received consultant fees from Cur, Elpis, Innocoll, SPARC, and SynDevRx; owns equity in Accurius, Enlight, and SynDevRx; is on the Board of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, and Tekla World Healthcare Fund; and received research grants from Boehringer Ingelheim and Sanofi. No funding or reagents from these companies were used in this study. B.R.R. reports serving on the advisory board for VincenTech which has no direct connection to the current research. The other authors have no competing interests to declare., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Cancer metastasis is a major contributor to patient morbidity and mortality 1 , yet the factors that determine the organs where cancers can metastasize are incompletely understood. In this study, we quantify the absolute levels of over 100 nutrients available across multiple tissues in mice and investigate how this relates to the ability of breast cancer cells to grow in different organs. We engineered breast cancer cells with broad metastatic potential to be auxotrophic for specific nutrients and assessed their ability to colonize different organs. We then asked how tumor growth in different tissues relates to nutrient availability and tumor biosynthetic activity. We find that single nutrients alone do not define the sites where breast cancer cells can grow as metastases. Additionally, we identify purine synthesis as a requirement for tumor growth and metastasis across many tissues and find that this phenotype is independent of tissue nucleotide availability or tumor de novo nucleotide synthesis activity. These data suggest that a complex interplay of multiple nutrients within the microenvironment dictates potential sites of metastatic cancer growth, and highlights the interdependence between extrinsic environmental factors and intrinsic cellular properties in influencing where breast cancer cells can grow as metastases., Competing Interests: Competing Interests R.F. consulted for Lime Therapeutics during this study, unrelated to the work presented. G.M.C. is a co-founder of Editas Medicine and has other financial interests listed at: https://arep.med.harvard.edu/gmc/tech.html. R.K.J. received consultant/SAB fees from DynamiCure, SPARC, SynDevRx; owns equity in Accurius, Enlight, SynDevRx; served on the Board of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, Tekla World Healthcare Fund, and received Research Grants from Boehringer Ingelheim and Sanofi; no funding or reagents from these organizations were used in the study. M.G.V.H. discloses that he is a scientific advisor for Agios Pharmaceuticals, iTeos Therapeutics, Sage Therapeutics, Pretzel Therapeutics, Lime Therapeutics, Faeth Therapeutics, Droia Ventures, MPM Capital and Auron Therapeutics. All remaining authors declare no competing interests.

Background: Hepatitis B virus (HBV) and Hepatitis C virus (HCV) show similarity in the transmission, distribution, hepatotropism, and leading to chronic asymptomatic infection. Coinfection of HBV and HCV can lead to more severe liver disease and an increased risk for progression to hepatocellular carcinoma (HCC). Most of the people with chronic infection are unaware of their HBV and HCV infections, hence facilitating these to go undiagnosed until these viruses have caused serious liver damage and they act as a potential source of infection for the community at large. Therefore, the present study aimed to find the prevalence of HBV and HCV along with incidences of coinfection of HBV and HCV in patients seeking hospital care in central India., Methods: A five-year hospital-based study was carried out at the tertiary care hospital in Central India from 2018 to 2022. A total of 72402 patients attending the outdoor patients and admitted indoor patients who were advised for HBV and HCV for screening before any invasive/surgical procedure and patients who presented with symptoms of acute or chronic liver disease were included in this study. Screening was done by immunochromatography-based card test followed by the confirmation of all samples by enzyme immunoassay., Results: Seroprevalence of HBV and HCV was found to be 3.71% and 1.91%, respectively. Coinfection with HBV/HCV was seen in 0.13% of the individuals. The overall prevalence of HBV, HCV, and HBV-HCV coinfection was significantly higher in the male population as compared to females., Conclusion: The study findings of seroprevalence of HBV and HCV among the hospital-based population will help to get a baseline understanding of the disease burden in central India. The HBV/HCV coinfection rate also raises serious concerns owing to its high prevalence rate among the younger age., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Family Medicine and Primary Care.)

Purpose: The purpose of this study was to evaluate risk factors associated with positive urine cultures following holmium laser enucleation of the prostate (HoLEP)., Materials and Methods: The data from a prospectively maintained database were analyzed to evaluate urine culture results following HoLEP and determine the contribution of predefined variables (age, prostate size, Charlson comorbidity score, surgical time [surrogate for case difficulty], the presence of a catheter preoperatively, postoperative urinary retention, and preoperative positive culture) on urine culture positivity at 60 days postoperatively. Statistical analyses included logistic regression and ANOVA., Results: The data from 136 subjects were included in the database and were evaluated at a median of 13.37 ± 6.72 months after their HoLEP. Postoperative positive cultures were noted in 23 subjects (16.91%). Preoperative positive cultures were found to predict positive postoperative urine cultures (odds ratio: 3.78, confidence interval: 1.18-12.78, P = 0.03). However, the preoperative and postoperative results were discordant in 9 of 14 subjects with both positive preoperative and postoperative cultures., Conclusions: Positive preoperative cultures were predictive of positive postoperative cultures. However, the pre- and postoperative results were often discordant. Host factors increasing susceptibility to bacteriuria may explain these findings., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Urology Annals.)

Introduction: Information on bioavailable Iron (BAI) content in respirable coal dust (RCD) is crucial to address occupational health and safety, especially in preventing coal workers' pneumoconiosis (CWP)., Materials and Methods: In the present study, we determined BAI concentrations in seventy-seven coal samples collected from ten coal mining regions of Central India. The cytotoxic potential of BAI-RCD was established invitro by using alveolar epithelial (A549) and macrophage (U937) cell lines. The oxidative/antioxidant status, inflammations, and genotoxicity attributed to BAI-RCD exposure were evaluated and correlated with CWP pathophysiology., Results: The mean BAI concentrations in the coal samples (n = 77) range from (275 to 9065 mg kg-1) and showed wide variability. Both cell lines were exposed to low (275 mg kg-1), moderate (4650 mg kg-1), and high (9065 mg kg-1) BAI-RCD samples showed significant (p < 0.001) cytotoxicity in a dose-dependent manner (low < moderate < high) compared to the control. After BAI-RCD treatment, both cell lines showed a decrease in antioxidant stress measures (SOD, CAT, and GSH) and a significant (p < 0.001) increase in oxidative stress parameters (NADPH, MPO, LPO, and PC). Furthermore, these cell line models demonstrated a statistically significant (p < 0.001) dose-dependent increase in cytokines (TGF-β1, IL-1β, TNF-α, MCP-1, and IL-6 cytokines) and oxidative DNA damage marker (8-OH-dG)., Conclusion: Results indicated that the central India coals (even at low BAI content) may be accountable for inflammatory responses and cytotoxicity. Hence, BAI can be important characteristic to establish safety standards for coal dust exposure before active mining., Competing Interests: The authors have declared that no competing interests exit., (Copyright: © 2024 Jain et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Surface roughness of arch wires directly impacts their corrosion behavior, friction resistance, and plaque accumulation, which may hinder tooth movement and lead to dental caries., Objectives: The study aims to synthesize vanillin-mediated silver nanoparticles (AgNPs), characterize them, assess surface roughness and cytotoxicity of arch wires after silver nanoparticle coating, and test their antibacterial properties., Materials and Methods: Nine copper-nickel-titanium arch wires (CuNiTi) were cut into equal pieces. Three were sent for surface roughness assessment, three for cytotoxicity, and three for antibacterial testing. Dip coating of wires was done using the sol-gel thin film method. The surface roughness (Ra) before and after coating was evaluated using scanning electron microscopy and atomic force microscopy. Cytotoxicity testing was done with a (3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay using gingival fibroblasts. Statistical analysis was done using SPSS software. Antibacterial activity against S. mutans was tested using the Agar-well diffusion method., Results: The CuNiTi wires were coated successfully, and the coating appeared homogeneous. The mean Ra after coating (297.3+/- 30.4 nm) was significantly less than that before coating (339.7+/-49.2 nm). AgNPs showed minimal cytotoxicity against human gingival fibroblasts at different concentrations. Optical microscopy showed over 90% viability between 12.5 and 100 µg/ml. At 100 µg/ml, only 80% of cells remained viable. AgNP coating is biocompatible at concentrations up to 75 µg/ml. There was a significant intergroup difference in the zone of inhibition (antibacterial activity) noted with higher values in noncoated wires. ( P value <0.007)., Conclusion: AgNPs coated on CuNiTi arch wires showed reduced surface roughness and minimal cytotoxic effects on human gingival cells and good antibacterial activity against S. mutans compared to noncoated arch wires., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Orthodontic Science.)

This review aimed at a systematic evaluation of the available literature on the effect of platelet-rich fibrin (PRF) in accelerating canine distal movement (CD). An elaborate search of the available literature on the effect of PRF on the acceleration of canine distal movement was conducted using appropriate search terms in PubMed, Scopus, Cochrane Central, and Google Scholar until April 2024. The risk of bias within the studies was assessed using the Cochrane risk of bias (RoB)-2 tool. Publication bias was assessed with a funnel plot, and a random effects model was used for quantitative synthesis. The certainty of the available evidence was assessed with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Following the systematic search, a total of 11 studies were included for the qualitative analysis, and three studies were included for quantitative synthesis. Most of the studies reported an increased rate of canine distal movement following administration of PRF. The overall pooled CD at one, two, three, four, and five months showed a significantly increased mean CD in i-PRF (p<0.00001; MD = 0.23; 95% CI: 0.14 to 0.32), and a significantly increased rate of CD was noted during the first and second months. The available studies had a moderate to low risk of bias and a moderate certainty of evidence. Hence, with a moderate certainty of evidence and a risk of bias, it can be concluded that PRF accelerates orthodontic tooth movement during the first two months., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Singh et al.)

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer without effective treatments. It is characterized by activating KRAS mutations and p53 alterations. However, how these mutations dysregulate cancer-cell-intrinsic gene programs to influence the immune landscape of the tumor microenvironment (TME) remains poorly understood. Here, we show that p53 R172H establishes an immunosuppressive TME, diminishes the efficacy of immune checkpoint inhibitors (ICIs), and enhances tumor growth. Our findings reveal that the upregulation of the immunosuppressive chemokine Cxcl1 mediates these pro-tumorigenic functions of p53 R172H . Mechanistically, we show that p53 R172H associates with the distal enhancers of the Cxcl1 gene, increasing enhancer activity and Cxcl1 expression. p53 R172H occupies these enhancers in an NF-κB-pathway-dependent manner, suggesting NF-κB's role in recruiting p53 R172H to the Cxcl1 enhancers. Our work uncovers how a common mutation in a tumor-suppressor transcription factor appropriates enhancers, stimulating chemokine expression and establishing an immunosuppressive TME that diminishes ICI efficacy in PDAC., Competing Interests: R.K.J. is a Consultant for Accurius, DynamiCure, and SynDevRx; owns equity in Accurius, Enlight, and SynDevRx; served on the Board of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, Tekla World Healthcare Fund and received a research Grant from Sanofi. No funding or reagents from these organizations were used in this study. S.S. is an SAB member for Related Sciences, Arcus Biosciences, Ankyra Therapeutics, Prox Bio, and Repertoire Immune Medicines. S.S. is a co-founder of Danger Bio. S.S. is a consultant for TAKEDA and Merck and receives funding for unrelated projects from Leap Therapeutics and iTeos Therapeutics. S.S.’s interests are reviewed and managed under MIT’s policies for potential conflicts of interest.

Objective: Current biomarkers for predicting immunotherapy response in non-small-cell lung cancer (NSCLC) are derived from invasive procedures with limited predictive accuracy. Thus, identifying a non-invasive predictive biomarker would improve patient stratification and precision immunotherapy., Methods and Analysis: In this retrospective multicohort study, the discovery cohort included 205 NSCLC patients screened from ORIENT-11 and an external validation (EV) cohort included 99 real-world NSCLC patients. The 'onion-mode segmentation' method was developed to extract 'onion-mode perfusion' (OMP) from contrast-enhanced CT images. The predictive performance of OMP or its combination with the PD-L1 Tumour Proportion Score (TPS) was evaluated by the area under the curve (AUC)., Results: High baseline OMP was associated with significantly longer survival and predicted patient response to combination anti-PD-(L)1 therapy in the discovery and EV cohorts. OMP complemented the PD-L1 TPS with superior predictive sensitivity (p=0.02). In the PD-L1 TPS<50% subgroup, OMP achieved an AUC of 0.77 for the estimation of treatment response (95% CI 0.66 to 0.86, p<0.0001). A simple bivariate model of OMP/PD-L1 robustly predicted therapeutic response in both the discovery (AUC 0.82, 95% CI 0.74 to 0.88, p<0.0001) and EV (AUC 0.80, 95% CI 0.67 to 0.89, p<0.0001) cohorts., Conclusion: OMP, derived from routine CT examination, could serve as a non-invasive and cost-effective biomarker to predict NSCLC patient response to immune checkpoint inhibitor-based therapy. OMP could be used alone or in combination with other biomarkers to improve precision immunotherapy., Competing Interests: Competing interests: RKJ received consultant fees from Cur, DynamiCure, Elpis, Innocoll, Merck, SPARC and SynDevRx; owns equity in Accurius, Enlight and SynDevRx; serves on the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund and Tekla World Healthcare Fund and received grants from Boehringer Ingelheim and Sanofi. Neither any reagent nor any funding from these organisations was used in this study. JS is an employee of Innovent Biologics. WX used to be an employee of Innovent Biologics. All the other authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Helical spin structures are expressions of magnetically induced chirality, entangling the dipolar and magnetic orders in materials 1-4 . The recent discovery of helical van der Waals multiferroics down to the ultrathin limit raises prospects of large chiral magnetoelectric correlations in two dimensions 5,6 . However, the exact nature and magnitude of these couplings have remained unknown so far. Here we perform a precision measurement of the dynamical magnetoelectric coupling for an enantiopure domain in an exfoliated van der Waals multiferroic. We evaluate this interaction in resonance with a collective electromagnon mode, capturing the impact of its oscillations on the dipolar and magnetic orders of the material with a suite of ultrafast optical probes. Our data show a giant natural optical activity at terahertz frequencies, characterized by quadrature modulations between the electric polarization and magnetization components. First-principles calculations further show that these chiral couplings originate from the synergy between the non-collinear spin texture and relativistic spin-orbit interactions, resulting in substantial enhancements over lattice-mediated effects. Our findings highlight the potential for intertwined orders to enable unique functionalities in the two-dimensional limit and pave the way for the development of van der Waals magnetoelectric devices operating at terahertz speeds., (© 2024. The Author(s).)

This study investigated the influence of relative humidity (RH) on the efficiency of SARS-CoV-2 RNA extraction using the Nextractor automated system. Experiments employing clinical samples demonstrated satisfactory sensitivity and reproducibility for RNA extraction at low humidity (below 50% RH). Conversely, extractions at high humidity (above 70% RH) resulted in complete failure of reverse transcription-polymerase chain reaction assays, with neither SARS-CoV-2 RNA nor the human RNase P gene (internal control) detected. Analysis suggested that residual ethanol, incompletely evaporating due to high humidity, acted as a potent polymerase chain reaction inhibitor in these samples. These findings highlighted the importance of maintaining optimal laboratory humidity (<50% RH) for reliable SARS-CoV-2 RNA extraction using the Nextractor system. Furthermore, laboratories should implement strategies such as regular humidity monitoring, staff training on humidity's impact, and system validation under specific humidity conditions to ensure accurate molecular diagnostic workflows for COVID-19 testing., Competing Interests: The authors declare no conflict of interest., (© 2024 The Journal of Biological Methods, All rights reserved.)